Alcohol and nicotine, found in tobacco products, are two of the most commonly used psychoactive substances and their excessive use remains at the top of the list of preventable causes of death. Epidemiological studies have consistently found tobacco and alcohol to have a very high rate of co-abuse, but it remains unclear precisely how the actions of nicotine affect the propensity to use ethanol and vice versa. One explanation for the co-abuse of these two drugs is that nicotinic acetylcholine receptors (nAChR) may represent a common site of action for ethanol and nicotine. The combination of these drugs may potentiate the rewarding effects produced by either drug alone. Our preliminary and published data have shown that the non-selective nAChR antagonist mecamylamine attenuates, while nicotine enhances, locomotor stimulation to ethanol in mice selectively bred for high locomotor stimulation to ethanol. Research in the field has also demonstrated that nicotine and ethanol can interact to cause synergist enhancement of dopamine levels in the nucleus accumbens (NACC), indicating that nicotine may enhance the rewarding effects of ethanol and contribute to the development of dependence. Long term neural effects of ethanol alone may be profoundly different from those of nicotine plus ethanol. The first goal of this proposal is to determine if nicotine potentiates the development of two ethanol-related behaviors: conditioned place preference (CPP) and behavioral sensitization (a measure of neuroadaptation). In addition, we propose to use autoradiography to measure binding at nAChR and RT-PCR to measure mRNA expression of nicotinic receptor genes in mice treated with chronic nicotine, ethanol and combined drug exposure. We hypothesize that nicotine will enhance the rewarding effects of ethanol and cause neuroadaptations at the level of behavior and nAChR that contribute to the high rate of comorbid use of these two drugs. The second goal of this proposal is to determine if pharmacological manipulation of nAChR alters the rewarding and neuroadaptive effects of ethanol. There are a limited number of effective pharmacological agents to treat alcohol and nicotine dependence. One preliminary but promising finding is that the FDA-approved smoking cessation drug varenicline (Chantix), a partial 42 nAChR agonist, decreased ethanol consumption in both rodents and humans. Although research indicates that varenicline reduces ethanol consumption, there is limited research focused on how varenicline affects other behaviors used to measure the rewarding effects of ethanol. Varenicline could influence ethanol consumption by reducing the rewarding effects of ethanol; however, varenicline could also increase the rewarding effects of ethanol and shift the dose response curve to the left, reducing the amount of alcohol needed to achieve the same level of reward. Thus, it is important to more critically evaluate the effects of varenicline on other ethanol- related behaviors; in this case we will examine CPP and behavioral sensitization. This will provide a better understanding of how to use this drug in a clinical setting for the treatment of alcohol dependence. PUBLIC HEALTH RELEVANCE: Alcohol and nicotine are two of the most commonly used psychoactive substances and their excessive use remains at the top of the list of preventable causes of death. The proposed work seeks to examine how nicotine and nAChR affect the development of ethanol-related behaviors that are associated with ethanol reward and neuroadaptation in an effort to understand why these two drugs share a high rate of co-abuse. Ultimately, the goal of this research is to understand the biological factors underlying alcohol and co-morbid nicotine dependence and to further evaluate one putative pharmaceutical treatment option, varenicline.